1. Field of the Invention
The present invention relates generally to the field of pharmacology and cancer treatment. Specifically, the present invention provides methods of cancer treatment using nebulized formulations of aerosolized liposomes containing camptothecins for delivery to the respiratory tract.
2. Description of the Related Art
Small particle liposome aerosol treatment consists of lipid-soluble or water-soluble anti-cancer drugs incorporated into liposomes, which are administered from aqueous dispersions in a jet nebulizer as disclosed in U.S. Pat. No. 5,049,388. Aerosols of 1-3 μm mass median aerodynamic diameter, generated upon nebulization, enable targeted delivery onto surfaces of the respiratory tract. The deposited liposomes subsequently release drug locally within the lung or into the blood circulation with delivery to extra-pulmonary tissue. If the drug is lipid soluble, it will associate with the lipid molecules in a manner specific to the lipid employed and to the anti-cancer drug employed and, possibly, may be modified further by various soluble constituents included in the suspending aqueous medium. Such soluble constituents may include buffering salts and possibly inositol to enhance the synthesis and secretion of surfactant phospholipid in lung tissue and to minimize respiratory distress already present or that which might result from the aerosol treatment (31). If the drug is water soluble, it may be incorporated by appropriate procedures in aqueous vesicles that exist in concentric spaces between lipid bilayers or lamellae of the multilamellar liposome. Unilamellar liposomes may be prepared; however, their capacity to entrap either lipid-soluble or water-soluble drugs is diminished since entrapment is restricted to one central vesicle.
Aerosol water droplets may contain one or more drug-liposomes. Nebulization shears liposomes to sizes readily discharged from the nozzle of the nebulizer. Liposomes up to several microns in diameter are typically sheared to diameters of less than 500 nm, and may be considerably smaller than that depending on the operating characteristics of the nebulizer and other variables. Shearing of water-soluble drugs contained in liposomes will release appreciable amounts of the water-soluble compound, perhaps 50 percent. This is not a contraindication to their use, but rather two forms of the drug preparation are administered. The effect includes the therapeutic effect that would be produced by both forms if either form had been given alone. Many other details of liposome aerosol treatment are described in U.S. Pat. No. 5,049,388. Moreover, it is also possible to incorporate more than one drug in an aerosol liposome treatment, either by mixing different drug-containing liposomes or by using liposomes wherein the drugs have been combined and incorporated together into liposomes.
One such drug is camptothecin (CPT), an inhibitor of topoisomerase-I, which is a plant alkaloid isolated from Camptotheca acuminata in 1966. Inhibitors of topoisomerase-I are potent antineoplastic drugs. Human cancer cells grown as xenografts in nude mouse models are greatly inhibited or may be eradicated after treatment with most camptothecin analogs (15). In clinical settings, camptothecins have been less effective (16). In comparison to mice, human metabolism of camptothecins yields a poor therapeutic index, which could explain the low response rate in cancer patients.
The anti-tumor activity of several of the camptothecins is diminished following dissolution in aqueous media. This is due to a hydrolyzable alpha-hydroxy lactone ring (ring E) which opens upon hydrolysis. The change results from acyl cleavage yielding the biologically inactive carboxylate form of the molecule. The lactone ring form of the drug is sheltered in liposomes, but pharmacokinetics of camptothecins in the presence of human serum albumin favors the inactive carboxylate form or open E-ring (17). This leads to rapid conversion of lactone to carboxylate in the presence of human serum albumin and, thus, to loss of anti-cancer activity.
Attempts to improve the therapeutic index of camptothecins using continuous infusion and oral administration have had limited success (18-20). Furthermore, increasing the exposure of cancer cells to the active lactone form or designing analogs with increased lactone stability to use in a clinical setting have not resulted in significant clinical improvement (21-26). In previous clinical studies of oral administration, the main toxicity profile of 9-NC was hematologic with anemia and neutropenia and gastrointestinal with nausea, vomiting and anorexia (28,29). Another difficult side effect of oral administration was chemical cystitis with hematuria (29).
The inventors have recognized a need in the art for methods of treating cancer in a human using camptothecins that avoids interaction with serum albumin or other constituents to preserve the anti-cancer effect of the camptothecins with significant reduction in toxicity. Specifically, the prior art is deficient in methods of treatment using formulations of aerosolized liposomes containing camptothecins that are deposited within the lungs on alveolar surfaces to effect treatment of the cancer. The present invention fulfills this long-standing need and desire in the art.